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BACKGROUND: Hemoglobin A(1c) (HbA(1c)) and fructosamine can be used to monitor glycemic control in diabetic patients with normal kidney function, but their validity in patients with chronic kidney disease (CKD) has not been evaluated. In this study, we evaluated the correlation and accuracy of these 2 measures of glycemic control in type 2 diabetic patients with CKD stages 3-4. STUDY DESIGN: Diagnostic test study. SETTING & PARTICIPANTS: Type 2 diabetic patients with normal (n = 30) and abnormal kidney function (n = 30) were recruited in Taipei Veterans General Hospital, Taiwan. INDEX TESTS: HbA(1c) and fructosamine. REFERENCE TEST: Self-monitoring of blood glucose levels. MEASUREMENTS: Blood glucose measurements consisted of 6 preprandial, 6 postprandial, and 2 bedtime assessments in a week with a cycle of 4-week intervals for 12 weeks. RESULTS: Correlation coefficients between HbA(1c) level or fructosamine-albumin ratio and mean blood glucose levels were 0.836 and 0.645 in participants with normal kidney function and 0.813 and 0.649 in participants with CKD stages 3-4, respectively. In patients with CKD stages 3-4, mean blood glucose levels in weeks 1-12 were 21.9 mg/dL (95% CI, 11.6-32.5) higher than estimated average glucose (eAG) levels calculated from HbA(1c) levels in participants with normal kidney function. In patients with CKD stages 3-4, mean blood glucose levels in weeks 10-12 were 15.5 mg/dL (95% CI, 5.2-30.5) higher than eAG levels calculated from fructosamine levels in participants with normal kidney function, but without statistical significance when eAG calculated from fructosamine level was corrected for serum albumin level (difference of 5.6 mg/dL; 95% CI, -8.6 to 19.8). LIMITATIONS: Relatively small number of participants with limited amount of blood glucose measurement data. CONCLUSION: Our data show that eAG calculated from HbA(1c) and fructosamine levels might underestimate mean blood glucose levels in patients with CKD stages 3-4. References ranges may need to be modified when interpreting results of measurements of glycemic control in type 2 diabetic patients with CKD. [ABSTRACT FROM AUTHOR]

Aim: Although Graves' disease (GD) is common in endocrine practices worldwide, global differences in diagnosis and management remain. We sought to assess the current practices for GD in countries across Asia and the Pacific (APAC), and to compare these with previously published surveys from North America and Europe., Methods: A web-based survey on GD management was conducted on practicing clinicians. Responses from 542 clinicians were received and subsequently analysed and compared to outcomes from similar surveys from other regions., Results: A total of 542 respondents participated in the survey, 515 (95%) of whom completed all sections. Of these, 86% were medical specialists, 11% surgeons, and 3% nuclear medicine physicians. In addition to serum thyroid-stimulating hormone (TSH) and free thyroxine assays, most respondents would request TSH-receptor autoantibody (TRAb) measurement (68%) during initial work-up. Thyroid ultrasound is requested by about half of respondents (53%), while the use of nuclear medicine scans is limited. The preferred first-line treatment is anti-thyroid drug (ATD) therapy (79%) with methimazole (MMI) or carbimazole (CBZ), followed by radioiodine (RAI; 19%) and surgery (2%). In case of surgery, one-third of respondents would opt for a subtotal rather than a total thyroidectomy. In case of mild Graves orbitopathy (GO), ATDs (67%) remains the preferred treatment, but a larger proportion of clinicians prefer surgery (20%). For a patient with intention to conceive, the preferred treatment pattern remained unchanged, although propylthiouracil (PTU) became the preferred ATD-agent during the first trimester. In comparison to European and American practices, marked differences were noted in the relatively infrequent usage of nuclear medicine scans and the overall higher use of a ATDs and β-blockers and adjunctive ATD-treatment during RAI in the APAC-group., Conclusion: Although regional differences regarding the diagnosis and management of GD are apparent in this first pan-Asia-Pacific survey, this study reveals the overall approach to the management of this disease in Asia-Pacific generally tends to fall between the trends appreciated in the American and European cohorts., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

A systematic review of genetic studies of thyroid disorders in Taiwan identified studies of gene mutations involved in the synthesis and binding of thyroid hormone, as well as mutations of proto-oncogenes and tumor suppressor genes in thyroid cancer. Studies related to gene polymorphisms in patients with autoimmune thyroid disease (AITD) and thyroid cancer were also reviewed. The most prevalent mutations in the Han-Chinese population were c.2268insT in the thyroid peroxidase (TPO) gene and c.919-2A>G in the Pendred syndrome (PDS) gene. Additional mutations have also been revealed in the genes encoding TPO (n = 5), thyroglobulin (TG; n = 6), pendrin (n = 2), and thyroxine-binding globulin (TBG; n = 2), which were novel at the time they were reported. The prevalence of various somatic mutations in differentiated thyroid cancer was similar in Taiwan and Western countries, with the RAS kinase mutation and tyrosine receptor kinase (TRK) and rearranged during transfection (RET) proto-oncogenes being detected in lower frequencies and the B-type RAF kinase (BRAF) mutation accounting for the majority of cases. Recent microRNA analysis revealed an association between miR146b and the BRAF mutation, which was associated with poor prognosis of papillary thyroid carcinoma (PTC). Susceptibility to Graves' disease (GD) was linked to the human leukocyte antigen (HLA) region. The associated alleles were different in Han-Chinese and Caucasians; HLA-DPB1*0501, the major allele in Taiwan, has a low frequency in the West. By contrast, a high frequency of HLA-DRB1*0301 was detected in Caucasians but not Han-Chinese. In addition to the HLA region, cytotoxic T lymphocyte-associated molecule-4 (CTLA4) gene polymorphisms +49G>A and +6230G>A (CT60) were positively associated with GD. The GG genotype and G allele of single nucleotide polymorphism (SNP) +49G>A were also related to relapse of Graves' hyperthyroidism after antithyroid drug withdrawal. Differences in the genetic patterns between Han-Chinese and Caucasians for some thyroid disorders suggest the importance of variable genetic influences in different populations., (Copyright © 2014. Published by Elsevier Taiwan.)

Background: Cleidocranial dysplasia is a rare hereditary skeletal disorder due to heterozygous loss of function mutations in the RUNX2 gene that encodes runt-related transcription factor 2 (RUNX2). Here we report a 52 year-old woman with cleidocranial dysplasia due to a novel RUNX2 mutation., Case Description: A 52 year-old Han Chinese woman presented with short stature and skeletal dysplasia that was first noted during early childhood. She was 153 cm in height and 40 kg in weight. Her skull was deformed with hypertelorism, midface hypoplasia, protrusion of chin, and dental abnormalities. Radiological examination revealed shortened clavicles and depressed skull bone and that were consistent with the clinical diagnosis of cleidocranial dysplasia. There was no family history of a similar skeletal disorder. We sequenced the RUNX2 gene and discovered a novel heterozygous mutation in exon 3 (c.476 del G, p.G159fs175X) that is predicted to cause a frameshift and premature termination that leads to the loss of the final 347 amino acid residues. This severely truncated protein is expected to be inactive., Literature Review: RUNX2 gene controls osteoblast differentiation and chondrocyte maturation. Around 90 RUNX2 mutations have been discovered in patients with cleidocranial dysplasia., Clinical Relevance: We identified a case of cleidocranial dysplasia due to a novel mutation of RUNX2 gene at exon 3 (c.476 del G).

Background: The incidence and risk factors of amiodarone-induced thyroid dysfunction are variable in the literature., Objective: The aim of this study was to investigate the clinical and biochemical features and risk factors of amiodarone-induced thyroid dysfunction in Taiwan., Setting: This study was conducted at a tertiary referral center for arrhythmia., Method: Retrospective analysis of patients treated with amiodarone during the years 2008-2009 was performed., Main Outcome Measure: Incidence and risk factors of amiodarone-induced thyrotoxicosis (AIT) and amiodarone-induced hypothyroidism (AIH) were assessed., Results: Of the 527 patients, 437 (82.9 %) remained euthyroid, 21 (4.0 %) developed AIT, and 69 (13.1 %) were affected with AIH. In univariate analysis, AIT was associated with younger age, and the risk factors for AIH included older age, higher baseline thyroid stimulating hormone (TSH) titer, lower baseline free T4 level, lower cumulative amiodarone dosage, and shorter amiodarone treatment duration. Cox regression analysis was performed to determine the different risk categories in the elderly population of age 65-74 (young-old), 75-84 (old-old), and ≥85 years old (oldest-old). Additionally increased risk of AIH was found in the groups of old-old (HR 2.09, 95 % CI 1.11-3.96) and oldest-old (HR 2.57, 95 % CI 1.21-4.75). In the multivariate analysis of risk factors for AIH, baseline TSH level (HR 1.38, 95 % CI 1.12-1.70) and cumulative amiodarone dosage (HR 0.95, 95 % CI 0.93-0.97) remained statistically significant., Conclusion: AIH was much more common than AIT in Taiwan, an area with sufficient iodine intake. Higher baseline TSH level was the predominant independent risk factor for the development of AIH.

A 4-month-old male baby was diagnosed with Permanent Neonatal Diabetes Mellitus. We identified a novel missense heterogeneous mutation in the KCNJ11 gene at codon 167 (aTC→tTC) in a region that corresponds to a predicted intracellular gate of the ATP-sensitive potassium channel., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: Patients with type 2 diabetes mellitus (T2DM) and peripheral arterial disease are classified as having very high cardiovascular risks. We therefore sought to determine whether assessments of the ankle brachial index (ABI) and brachial ankle pulse wave velocity (baPWV) together exhibited a superior association with the outcomes of T2DM., Methods: A retrospective analysis of patients receiving ABI and baPWV during the period 2005-2007 was performed. Patients A total of 452 subjects were enrolled and followed-up for a mean 5.8 years after being grouped according to the ABI (<0.9 vs. ≥0.9) and baPWV (<1,700 cm/s vs. ≥1,700 cm/s)., Results: The outcomes were all-cause mortality and composite events (all-cause mortality, hospitalization for coronary artery disease, stroke, re-vascularization, amputation and diabetic foot). Inter-group differences in the smoking rate, duration of diabetes, systolic and pulse blood pressure, anti-platelet drugs, estimated glomerular filtration rate, and urine albumin excretion were significant. During the follow-up period, 17 (3.7%) individuals died and composite events were recorded in 64 cases (14.1%). A low ABI plus high baPWV was found be associated with poor outcomes compared with a normal ABI plus low baPWV (p<0.001). Meanwhile, a low ABI plus high baPWV was associated with an increased risk of all-cause mortality [hazard ratio (HR) 17.01, 95% confidence interval (CI) 1.57-183.73, p=0.019] and composite events (HR 8.53, 95% CI 3.31-21.99, p<0.001)., Conclusion: In this study, the outcomes of patients with a low ABI plus high baPWV were the worst, while the subjects with a low ABI plus low baPWV or normal ABI exhibited similar outcomes. Therefore, the ABI plus baPWV exhibits a better association with the outcomes of T2DM.

Background: Adrenocortical carcinoma is a rare malignancy and rare cause of Cushing's syndrome., Case Presentation: A 65-year-old seemingly well male patient was referred to our clinic under the suspicion of hyperaldosteronism due to hypertension combined with hypokalemia. However, his serum aldosterone and plasma renin activity were within normal limits. Instead, Cushing's syndrome was diagnosed by elevated urine free cortisol and a non-suppressible dexamethasone test. Abdominal computed tomography showed a 7.8 × 4.8 cm mass lesion at the right adrenal gland with liver invasion. Etomidate infusion was performed to reduce his cortisol level before the patient received a right adrenalectomy and liver wedge resection. The pathology report showed adrenocortical carcinoma with liver and lymph node metastasis. According to the European Network for the Study of Adrenal Tumors (ENSAT) staging system, the tumor was classified as T4N1M1, stage IV. Recurrent hypercortisolism was found shortly after surgery. The patient died of Fournier's gangrene with septic shock on the 59th day after diagnosis., Conclusions: We report a case of rapidly progressive stage IV adrenocortical carcinoma with initial presentations of hypokaelmia and hypertension, mimicking hyperaldosteronism.

Objective: To investigate the mutations in the SLC26A4 gene in a Chinese patient with Pendred syndrome., Methods: The diagnosis of Pendred syndrome was confirmed by the family history, pure tone audiogram, perchlorate discharge test (PDT), and computed tomography (CT) of the temporal bone. DNA extraction, PCR and DNA sequencing were performed according to standard procedures. Mutations in the SLC26A4 gene were compared with 100 unrelated subjects to exclude common polymorphism. Splice-site mutation was further confirmed by restriction enzyme length polymorphism (RFLP) with the specifically designed primers., Results: The proband presented with typical features of bilateral sensorineural deafness since childhood and goiter development in the early adulthood. Thyroid studies disclosed euthyroidism with elevated thyroglobulin, but negative for PDT. Marked enlargement of bilateral vestibular aqueduct (>1.5 mm) was found by CT of the temporal bone. A novel SLC26A4 splice-site mutation c.1263+1G>A (IVS10+1G>A) was identified in compound heterozygosity with the missense mutation c.1079C>T (p.A360V) in the proband. Both mutations were not found in the 100 unrelated Chinese., Conclusions: Our results support previous findings that Pendred syndrome can be caused by compound heterozygous mutation in the SLC26A4 gene, in which IVS10+1G>A is a novel pathogenic mutation., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

In cirrhosis, the development of ascites and the response to diuretics are determined by the RAAS (renin-angiotensin-aldosterone system) and renal sodium handling system. We hypothesized that SNPs (single nucleotide polymorphisms) affecting candidate genes in the RAAS and renal sodium handling pathway may influence initial diuretic responsiveness and affect clinical outcome in non-azotaemic cirrhotic patients with moderate ascites. We prospectively recruited 176 patients and 245 controls and determined their genetic polymorphisms for 24 SNPs of ten genes involved in the RAAS and renal sodium handling pathway. In cirrhotic patients with moderate ascites, multivariate analysis showed that diuretic unresponsiveness was predicted by a high basal plasma aldosterone level, by a high aldosterone/renin ratio and by specific risk genotypes of ACE (gene encoding angiotensin-converting enzyme), CYP11B2 (gene encoding aldosterone synthase) and ADDA (gene encoding α-adducin). This association between genetic polymorphisms and diuretic unresponsiveness was confirmed by an independent validation cohort. Notably, additive effects in relation to diuretic unresponsiveness were observed in cases where there was the simultaneous presence of the three risk genotypes. Among patients carrying any of the risk genotypes, more episodes of paracentesis and ascites-related readmission after 3 months of treatment, as well as a reduced 1-year survival rate, were observed. In addition to traditional predictors, our present study provides additional genetic and neurohormonal predictors that will help to identify diuretic non-responders among cirrhotic patients with moderate ascites. Among those carrying unfavourable risk genotypes, additional therapies, including paracentesis and albumin infusion, should be started as early as possible.

Objective The six core competencies designated by Accreditation Council for Graduate Medical Education (ACGME) are essential for establishing a patient centre holistic medical system. The authors developed a faculty programme to promote the postgraduate year 1 (PGY(1)) resident, ACGME six core competencies. The study aims to assess the clinical instructors' perception, attitudes and subjective impression towards the various sessions of the 'faculty development programme for teaching ACGME competencies.' Methods During 2009 and 2010, 134 clinical instructors participated in the programme to establish their ability to teach and assess PGY(1) residents about ACGME competencies. Results The participants in the faculty development programme reported that the skills most often used while teaching were learnt during circuit and itinerant bedside, physical examination teaching, mini-clinical evaluation exercise (mini-CEX) evaluation demonstration, training workshop and videotapes of 'how to teach ACGME competencies.' Participants reported that circuit bedside teaching and mini-CEX evaluation demonstrations helped them in the interpersonal and communication skills domain, and that the itinerant teaching demonstrations helped them in the professionalism domain, while physical examination teaching and mini-CEX evaluation demonstrations helped them in the patients' care domain. Both the training workshop and videotape session increase familiarity with teaching and assessing skills. Participants who applied the skills learnt from the faculty development programme the most in their teaching and assessment came from internal medicine departments, were young attending physician and had experience as PGY(1) clinical instructors. Conclusions According to the clinical instructors' response, our faculty development programme effectively increased their familiarity with various teaching and assessment skills needed to teach PGY(1) residents and ACGME competencies, and these clinical instructors also then subsequently apply these skills.

The present study was aimed to investigate glucose homeostasis and insulin secretion in acromegalic patients during octreotide-long acting release (LAR) therapy and designed as an observational prospective study. 18 acromegalic patients who had undergone trans-sphenoidal surgery with active disease were included. All patients were treated with octreotide-LAR injection for 1 year. These patients received oral glucose tolerance test (OGTT) before, 21 days after, and 1 year after octreotide-LAR treatment. Primary outcomes were changes in glucose levels and insulin secretion during an OGTT. We also determined the differences between subjects with normalized and uncontrolled IGF-1 levels. Of the 18 patients treated with octreotide-LAR for 1 year, 89% achieved fasting GH levels <2.5 μg/l, 85% reached the nadir GH concentration <1 μg/l, and 61% achieved normal age- and sex-matched IGF-1 values. 21 days after one dose of octreotide-LAR injection, insulin response during OGTT significantly decreased, and the Matsuda index increased significantly. One year after octreotide-LAR therapy, most parameters of glucose homeostasis returned to baseline levels. However, insulin response during OGTT at 30 and 60 min, and the insulinogenic index were still significantly decreased. Compared with the IGF-1-normalized group, the IGF-1 uncontrolled group had the same fasting GH and nadir GH levels and a higher insulin AUC and total insulin secretion. During octreotide-LAR treatment, the early-phase insulin response to OGTT is reduced and plasma glucose levels remained normal in most patients. The IGF-1 uncontrolled group had the same fasting GH and nadir GH levels during OGTT, but had better glucose homeostasis., (© Georg Thieme Verlag KG Stuttgart · New York.)

Mutations in the phosphate-regulating endopeptidase homolog, X-linked, gene (PHEX), which encodes a zinc-dependent endopeptidase that is involved in bone mineralization and renal phosphate reabsorption, cause the most common form of hypophosphatemic rickets, X-linked hypophosphatemic rickets (XLH). The distribution of PHEX mutations is extensive, but few mutations have been identified in Chinese with XLH. We extracted genomic DNA and total RNA from leukocytes obtained from nine unrelated Chinese subjects (three males and six females, age range 11-36 years) who were living in Taiwan. The PHEX gene was amplified from DNA by PCR, and the amplicons were directly sequenced. Expression studies were performed by reverse-transcription PCR of leukocyte RNA. Serum levels of FGF23 were significantly greater in the patients than in normal subjects (mean 69.4 ± 18.8 vs. 27.2 ± 8.4 pg/mL, P < 0.005), and eight of the nine patients had elevated levels of FGF23. Germline mutations in the PHEX gene were identified in five of 9 patients, including novel c.1843 delA, donor splice site mutations c.663+2delT and c.1899+2T>A, and two previously reported missense mutations, p.C733Y and p.G579R. These data extend the spectrum of mutations in the PHEX gene in Han Chinese and confirm variability for XLH in Taiwan.

Objectives: To identify mutations in the KAL1, the KAL2, and PROKR2/PROK2 genes and to characterize phenotypic features in 5 Chinese subjects with Kallmann Syndrome (KS) and 6 subjects with normosmic hypogonadotrophic hypogonadism (NHH) in Taiwan., Design and Patients: Five unrelated males (age range 22-52 yr) with clinical manifestations of KS and 6 unrelated males (age range 24-47 yr) with NHH were analyzed. In addition, 5 relatives of KS subjects were also evaluated. Genomic DNA extraction, PCR, and DNA sequence analyses were performed using standard procedures., Results: The 1st patient had a single missense mutation in his copy of the KAL1 gene, a T→G transversion in codon 134 that results in replacement of cysteine by gly cine. The 2nd affected subject had a single missense mutation in the KAL1 gene, a T→C transition in codon 163 that results in replacement of cysteine by arginine. The 3rd case was hemizygous for a nonsense mutation in codon 424 of exon 9 (c.CGA→TGA) of the KAL1 gene. This mutation predicts a markedly truncated protein. Two of the mutations (p.C134G and p.C163R) we identified in the KAL1 gene are novel., Conclusions: We identified 3 mutations, including 2 novel mutations, in the KAL1 gene in patients with KS in Taiwan. These data extend the variety of KAL1 gene mutations in KS and further define the role of the KAL1 protein in olfactory bulb development.

Background: Thyroglobulin (TG) defect is a rare cause of congenital hypothyroidism. Although only 44 mutations of the human TG gene have been identified, we have suspected a TG defect in 38% of Taiwan Chinese children/adolescents presenting with moderate or severe thyroidal dyshormonogenesis., Study Objective: The aim of the study is to report the discovery of new TG gene mutations and associated clinical manifestations of the defective TG protein., Patients and Results: In seven patients from six families, we detected six new TG gene mutations, including c.1348delT, p.R432X (c.1351C>T), g.IVS3 + 2T>G, c.1712delT, p.Q1765X (c.5350C>T), and c.6047delA. The c.1348delT and p.R432X mutations were the most common, detected in 33 and 25%, respectively, of alleles studied. Haplotype analysis suggested that the c.1348delT and g.IVS3 + 2T>G mutations are due to founder effects, whereas p.R432X is probably due to independently recurrent de novo mutations. mRNA transcript of the g.IVS3 + 2T>G mutant, detected in whole blood by reverse transcription-nested PCR, showed skipping of exon 3 (98-bp deletion) and a frameshift, with a terminal signal after 17 altered amino acid residues., Conclusions: TG defects have an important role in severe thyroidal dyshormonogenesis (pretreatment, or after a 3-wk T(4) withdrawal, plasma T(4) < or = 30 nmol/liter) in Taiwanese. Its genetic characteristics are markedly different from those described in other populations presenting with mutations of the TG gene.

Context: Mutations that inactivate one allele of the gene encoding the calcium sensing receptor (CaSR) cause autosomal dominant familial hypocalciuric hypercalcemia (FHH), whereas homozygous mutations cause neonatal severe hyperparathyroidism., Objective: We describe the identification and biochemical characterization of a novel CASR gene mutation that caused apparent autosomal recessive FHH in an extended consanguineous kindred., Design: The study design involved direct sequence analysis of the CaSR gene, clinical and biochemical analyses of patients, and in vitro immunobiochemical studies of the mutant CaSR., Results: A novel inactivating mutation (Q459R) was identified in exon 4 of both alleles of the CASR in the proband, who presented with asymptomatic hypercalcemia and hypocalciuria at age 2 yr. The proband's parents were heterozygous for the Q459R mutation consistent with autosomal recessive inheritance of FHH. Among 13 family members that were studied, eight subjects were heterozygous for the Q459R mutation and five had normal genotypes. All heterozygous subjects were asymptomatic and normocalcemic apart from one subject who was mildly hypercalcemic. The Q459R mutant CaSR was normally expressed at the cell membrane but retained only 30-50% of the calcium-dependent activity of the wild-type CaSR., Conclusion: We identified a novel loss-of-function Q459R mutation in the CASR gene that exhibits mildly reduced sensitivity to calcium and that is associated with apparent autosomal recessive transmission of FHH. This study demonstrates the importance of genetic testing in FHH to distinguish between de novo and inherited mutations of the CASR gene and assist in management decisions.

Objective: To evaluate whether treatment with insulin is advantageous compared with oral antidiabetes agents in newly diagnosed type 2 diabetes with severe hyperglycemia after short-term intensive insulin therapy., Research Design and Methods: Newly diagnosed type 2 diabetic patients with severe hyperglycemia were hospitalized and treated with intensive insulin injections for 10-14 days. The oral glucose tolerance test (OGTT) was performed after intensive insulin treatment. After discharge, the patients were randomized to receive either insulin injections or oral antidiabetes drugs (OADs) for further management. The OGTT was repeated 6 months later, and beta-cell function and insulin sensitivity were evaluated again. These subjects were continually followed up for another 6 months to evaluate their long-term glycemic control., Results: At the 6th month of the study, the A1C level was significantly lower in the insulin group than in the OAD group (6.33 +/- 0.70% vs. 7.50 +/- 1.50%; P = 0.002). During the follow-up visit, the A1C level was still better in the insulin group (6.78 +/- 1.21% vs. 7.84 +/- 1.74%; P = 0.009). All parameters regarding beta-cell function measured in the OGTT were improved significantly in both groups after 6 months of treatment. Compared with the OAD group, the homeostasis model assessment of beta-cell function index, insulin area under the curve, and insulinogenic index were better in the insulin group., Conclusions: A 6-month course of insulin therapy, compared with OAD treatment, could more effectively achieve adequate glycemic control and significant improvement of beta-cell function in new-onset type 2 diabetic patients with severe hyperglycemia.

Background: Hirschsprung's disease (HSCR), or aganglionic megacolon, is a hereditable disease of the enteric nervous system. It is an embryonic developmental disorder characterized by the absence of ganglion cells in the lower enteric plexus. Gut motility is compromised in HSCR, with consequent risk of intestinal obstruction., Methods: We sequenced the RET gene and characterized the clinical manifestations in 15 unrelated Chinese patients (9 males, 6 females; age range, 2-21 years) with sporadic HSCR. Genomic DNA extraction, PCR and DNA sequence analysis were performed according to standard procedures., Results: We identified heterozygous RET gene mutations in 2 patients. The mutations included a missense mutation in exon 2 (CGC --> CAC) resulting in a substitution of arginine by histidine at codon 67 (patient 1), and a missense mutation in exon 3 (TAC --> AAC) resulting in a substitution of tyrosine by asparagine at codon 146 (patient 2). The pathological findings disclosed short-segment HSCR in patient 1 and long-segment HSCR in patient 2, respectively., Conclusion: We identified RET gene mutations in 2 of 15 patients with HSCR in Taiwan. The Y146N mutation we identified was novel.

Aim: Self-monitoring of blood glucose (SMBG) is important for patients treated with insulin to detect asymptomatic hypoglycaemia and to guide patients towards reaching blood glucose goal. This study compared two management programs for adjusting bedtime insulin dose: program 1 (performed by study subjects) vs. program 2 (performed by study subjects and reminded by investigators)., Methods: This is a prospective, open-level, 28-week randomized trial in poorly controlled type 2 diabetic subjects. One hundred subjects treated with oral antidiabetic drugs plus bedtime insulin with glycated haemoglobin A(1C) (A1C) >8.0% were screened and received a structure education package in a 4-week run-in period. Seventy-eight subjects were randomized to two treatment programs (adjust insulin dose by themselves with or without investigators' reminder) and reviewed by the investigators at a 4-week interval clinical visit., Results: The mean SMBG decreased significantly in both groups, with a greater decrease observed in program 2 vs. program 1 (from 198.7 +/- 43.1 to 122.6 +/- 21.9 mg/dl vs. from 194.0 +/- 42.7 to 151.6 +/- 37.7 mg/dl, p < 0.001). Bedtime insulin dose increased in both groups with a greater increase in program 2 (from 14.4 +/- 8.7 to 27.4 +/- 12.8 IU vs. from 14.3 +/- 8.3 to 18.4 +/- 6.2 IU, p < 0.001). There was a significant reduction in A1C from 9.54 +/- 1.67% to 7.76 +/- 1.27%, with a greater decrease (p < 0.001) in program 2 (2.17%) than in program 1 (1.40%). There were more subjects in the program 2 group achieving the treating targets: mean SMBG < or =120 mg/dl (46.9 vs. 17.9%) and A1C < or =7.0% (54.5 vs. 32.2%). There was no significant difference in the incidence of hypoglycaemia and body weight changes., Conclusions: Systematically titrating bedtime insulin dose added to oral therapy, especially combined with health care reminders, can safely improve glycaemic control in type 2 diabetes with poor glycaemic control. This regimen may facilitate safe and effective insulin therapy in routine medical practice and improve achievement of recommended standards of diabetes care.

Objective: To investigate whether the effects of regular diabetes health education or a holiday-specific pamphlet before the Chinese New Year holiday period could improve glycemic control during the winter holidays among patients with type 2 diabetes mellitus., Study Design: Randomized controlled trial., Methods: The study was conducted from October 2004 to December 2005 in Taipei Veterans General Hospital. Subjects were randomized to program 1 (receipt of regular diabetes education between October 20 and November 25, 2004, and then every 3-4 months) or to program 2 (receipt of a special reminder pamphlet during the holidays). The patients were seen and blood samples obtained on 4 occasions during the holidays and then every 4 months through December 2005., Results: Ninety-three subjects completed the first 4 visits during the Chinese New Year holidays, and 89 subjects completed 12 months of the study. Fructosamine levels in program 1 increased more during the preholiday period than those in program 2 (mean [standard deviation] 7.4 [5.2] vs -5.3 [8.3] mumol/L, P = .03) during the preholiday period. Changes in fructosamine levels during the holiday and postholiday periods were similar in the 2 groups. At the end of the holidays, changes in glycosylated hemoglobin (A1C) levels were 0.34% (95% confidence interval, 0.03%-0.85%) in program 1 and 0.09% (95% confidence interval, -0.23% to 0.42%) in program 2. After the Chinese New Year holidays, the groups had similar changes in A1C levels, with a slight downward decline thereafter., Conclusion: A special educational reminder pamphlet for the holidays led to improvements in glycemic control during the Chinese New Year holidays.

Aims: The purpose of this study was to determine the relationship between subclinical hypothyroidism and prevalence of retinopathy and nephropathy, incident cardiovascular disease, and mortality in Type 2 diabetic patients without taking thyroid medication., Methods: Serum thyrotropin and free thyroxine concentrations were measured in 588 Type 2 diabetic subjects in Taipei Veterans General Hospital, Taiwan. In a cross-sectional study, we examined the prevalence of retinopathy and nephropathy. In a longitudinal study, we examined the risk of cardiovascular disease events, cardiovascular mortality and total mortality in the 4-year follow-up., Results: In the cross-sectional analysis, subclinical hypothyroidism was associated with a greater prevalence of diabetic nephropathy (odds ratio, 3.15 [95% CI, 1.48-6.69]) and did not show a high prevalence of diabetic retinopathy (odds ratio, 1.15 [95% CI, 0.59-2.26]) compare to euthyroid diabetics. During the 44.0 +/- 7.4 months of follow-up, 51 participants had cardiovascular events. The risk of cardiovascular events was significantly increased in Type 2 diabetics with subclinical hypothyroidism after adjustment for age, sex, A1C, other standard cardiovascular risk factors and medication (hazard ratio, 2.93; 95% CI, 1.15-7.48; P = 0.024), but it became nonsignificant after additional adjustment for urinary albumin-to-creatinine ratio (hazard ratio, 2.06; 95% CI, 0.67-6.36; P = 0.211). The rates of cardiovascular-related and total mortality did not significantly differ by thyroid status., Conclusions: Type 2 diabetic patients with subclinical hypothyroidism are associated with an increased risk of nephropathy and cardiovascular events, but not with retinopathy. Our data suggest that the higher cardiovascular events in subclinical hypothyroidism with Type 2 diabetes may be mediated with nephropathy.

Pendred syndrome (PS) is an autosomal recessive disease that is characterized by congenital sensorineural hearing loss, goiter, and a partial iodine organification defect. In this study, we characterized the thyroid status and identified mutations in the SLC26A4 gene in Chinese subjects with PS. We evaluated 7 unrelated Chinese subjects who had PS. Biochemical analysis, formal audiogram, ultrasonography of the thyroid gland, perchlorate discharge test, computerized tomography scan of the vestibular aqueducts, and DNA sequence analysis of SLC26A4 were performed. Levels of thyroid hormones were essentially normal in all patients: 2 patients had goiters and/or elevated serum thyroglobulin levels, whereas 2 other patients had positive thyroid antibodies and a positive perchlorate discharge test. We identified SLC26A4 gene mutations in 6 of 7 probands and their affected relatives. The affected subjects in family I was compound heterozygous for 2 missense mutations: a mutation in exon 9 (1079C>T) that resulted in the replacement of alanine by valine at codon 360 (A360V) and a mutation in exon 19 (2168A>G) that resulted in the replacement of histidine by arginine at codon 723 (H723R). The affected subjects in families II and III all were homozygous for a mutation in intron 7. The probands IV and V were compound heterozygotes for the mutation in intron 7 and in exon 19, and the proband VI was compound heterozygous for the intron 7 mutation and a missense mutation in exon 12 (1343C>T) that resulted in the replacement of serine by leucine at codon 448 (S448L). One novel mutation was identified (A360V). We identified biallelic mutations in the SLC26A4 gene in 6 of 7 probands with PS in Taiwan, including a novel missense mutation. The mild thyroid dysfunction in these patients suggests that PS should be considered in all patients with congenital or early-onset hearing impairment.

Background: A unique genomic difference between human and civet severe acute respiratory syndrome coronaviruses (SARS-CoVs) is that the former has a deletion of 29 nucleotides from open reading frame (orf) 8a' that results in the generation of orf8a and orf8b. The objectives of the present study were to analyze antibody reactivity to ORF8a in patients with SARS and to elucidate the function of ORF8a., Methods: Western-blot and immunofluorescent antibody assays were used to detect anti-ORF8a antibody. SARS-CoV HKU39849 was used to infect stable clones expressing ORF8a and cells transfected with small interfering RNA (siRNA). The virus loads (VLs) and cytopathic effects (CPEs) were recorded. Confocal microscopy and several mitochondria-related tests were used to study the function of ORF8a., Results: Two (5.4%) of 37 patients with SARS had anti-ORF8a antibodies. The VLs in the stable clones expressing ORF8a were significantly higher than those in control subjects 5 days after infection. siRNA against orf8a significantly reduced VLs and interrupted the CPE. ORF8a was found to be localized in mitochondria, and overexpression resulted in increases in mitochondrial transmembrane potential, reactive oxygen species production, caspase 3 activity, and cellular apoptosis., Conclusions: ORF8a not only enhances viral replication but also induces apoptosis through a mitochondria-dependent pathway.

Mutations in the CYP17 gene impair steroid biosynthesis in the adrenals and gonads, resulting in 17alpha-hydroxylase/17,20-lyase (P450c17) deficiency, leading to amenorrhea, sexual infantilism, hypokalemia, and hypertension. To date, more than 50 mutations in the CYP17 gene associated with congenital adrenal hyperplasia have been described. In this study, we analyzed a 36-year-old phenotypic female, genotypic male, with P450c17 deficiency to compare with an additional group of 50 Chinese subjects without P450c17 deficiency in Taiwan. DNA sequence analysis of the CYP17 gene was performed. The result showed that the proband had a compound heterozygous mutations in exon 6 (CGC-->TGC) that resulted in the substitution of arginine by cysteine at codon 362, and in exon 7 (CCG-->CGG) that resulted in the substitution of proline by arginine at codon 409. In conclusion, we have identified a compound heterozygous mutation in the CYP17 gene in one patient with congenital adrenal hyperplasia in Taiwan.

Objective: Noninsulinoma pancreatogenous hypoglycaemia syndrome (NIPHS), characterized by postprandial neuroglycopaenia, negative prolonged fasts and negative perioperative localization studies for insulinoma, but positive selective arterial calcium stimulation tests and nesidioblastosis in the gradient-guided resected pancreas, is a rare hypoglycaemic disorder of undetermined aetiology. We analysed the clinical, morphological and immunohistological features to further clarify the aetiology and pathogenesis of this rare disease., Patients: Ten consecutive patients with NIPHS (nine men and one woman, aged 29-78 years) were included in the study. Six of the 10 received a gradient-guided subtotal (70%) or distal (50%) pancreatectomy. In the remaining four patients, diazoxide treatment was initiated and the precise mechanism of its action was assessed by meal tests., Results: All of the patients showed a combination of postprandial neuroglycopaenia, negative prolonged fasts (except one patient) and negative localization studies for insulinoma, but positive calcium stimulation tests and nesidioblastosis in the gradient-guided resected pancreas. Immunohistological studies of the resected pancreatic tissues revealed neither an increased rate of proliferation of beta-cells nor an abnormal synthesis and/or processing of either proinsulin or amylin. Evidence of overexpression of the two pancreatic differentiation factors, PDX-1 and Nkx-6.1, as well as the calcium sensing receptor (CaSR) was absent. Nevertheless, abnormal expression of islet neogenesis-associated protein (INGAP), a human cytokine expressed only in the presence of islet neogenesis, in ducts and/or islets, was identified in three of the five patients studied. All of the six patients who received a surgical operation were relieved of further neuroglycopaenic attacks, but one patient who received a subtotal pancreatectomy developed diabetes. In the remaining four patients who received diazoxide treatment, hypoglycaemic episodes were satisfactorily controlled with an attenuated response of beta-cell peptides to meal stimulation., Conclusions: Our results strengthen the existence of this unique clinical hypoglycaemic syndrome from beta-cell hyperfunction as well as the value of the selective arterial calcium stimulation test in its correct diagnosis and localization. The mechanisms underlying beta-cell hyperfunction and release of insulin to calcium, however, remain poorly characterized. Nevertheless, in a subset of patients with NIPHS, there exists some, as yet undefined, pancreatic humoral/paracrine factor(s) other than proinsulin, amylin, PDX-1, Nkx-6.1 and possibly glucagon-like peptide-1 (GLP-1) that are capable of inducing the INGAP gene and, if activated, will initiate ductal proliferation and islet neogenesis. As for the treatment, we recommend that diazoxide be tried first in each patient and, should it fail, a gradient-guided subtotal or distal pancreatectomy be attempted.

Background: This study compares the cardiovascular autonomic function in type 2 diabetes with and without microalbuminuria, in order to identify the possible links between early nephropathy and diabetic autonomic neuropathy (DAN)., Methods: Cardiovascular reflex tests were performed to determine the cardiovascular autonomic function. Thirty cases of type 2 diabetes with microalbuminuria were studied for evidence of DAN to compare with a normoalbuminuric group of 56 diabetic patients., Results: There was an increased prevalence of autonomic dysfunction in patients with microalbuminuria (63.3% in the microalbuminuria group vs. 40.0% in the normoalbuminuric controls, p = 0.001). These patients had lower heart rate variability during single breathing tests (6.9 +/- 4.3 vs. 9.6 +/- 3.6 beats/minute, p = 0.005), during 6 consecutive breathings (5.8 +/- 3.6 vs. 8.2 +/- 3.3 beats/minute, p = 0.005), after standing up (12.2 +/- 4.6 vs. 15.0 +/- 5.2 beats/ minute, p = 0.012), and during the Valsalva maneuver (11.3 +/- 3.5 vs. 13.2 +/- 3.6 beats/minute, p = 0.022). The heart rate variability with these stresses was revealed to be less favorable in subjects with microalbuminuria. However, blood pressure (BP) changes from the sitting to standing position were not significantly different for systolic BP (11.5 +/- 10.7 vs. 10.7 +/- 7.8 mmHg, p = 0.741) and diastolic BP (5.2 +/- 4.4 vs. 5.9 +/- 4.0 mmHg, p = 0.451) between the 2 groups., Conclusion: Type 2 diabetic patients with microalbuminuria have diminished heart rate variability in response to deep breathing, change of position and the Valsalva maneuver, but they preserve BP response to postural change. Therefore, microalbuminuria seems to be associated with early DAN, but not with advanced DAN.

Multiple endocrine neoplasia type 1 (MEN1) is characterized by parathyroid, enteropancreatic endocrine and pituitary adenomas as well as germline mutation of the MEN1 gene. We describe 2 families with MEN1 with novel mutations in the MEN1 gene. One family was of Turkish origin, and the index patient had primary hyperparathyroidism (PHPT) plus a prolactinoma; three relatives had PHPT only. The index patient in the second family was a 46-yr-old woman of Chinese origin living in Taiwan. This patient presented with a complaint of epigastric pain and watery diarrhea over the past 3 months, and had undergone subtotal parathyroidectomy and enucleation of pancreatic islet cell tumor about 10 yr before. There was also a prolactinoma. Sequence analysis of the MEN1 gene from leukocyte genomic DNA revealed heterozygous mutations in both probands. The Turkish patient and her affected relatives all had a heterozygous A to G transition at codon 557 (AAG-->GAG) of exon 10 of MEN1 that results in a replacement of lysine by glutamic acid. The Chinese index patient and one of her siblings had a heterozygous mutation at codon 418 of exon 9 (GAC-->TAT) that results in a substitution of aspartic acid by tyrosine. In conclusion, we have identified 2 novel missense mutations in the MEN1 gene.

Familial hypercholesterolemia (FH) is inherited as an autosomal dominant trait that has been associated with more than 920 different mutations in the low-density lipoprotein receptor (LDLR) gene. To characterize LDLR gene mutations in the Chinese of Han descent with FH, we isolated genomic DNA from peripheral blood samples of 20 affected subjects and 50 healthy subjects with no family history of hypercholesterolemia. We used polymerase chain reaction and long polymerase chain reaction to amplify the 18 coding exons and the minimal promoter of the LDLR gene, and subjected amplicons to direct sequence analysis. We identified 6 mutations in LDLR gene, including heterozygous missense mutations I420T (ATC-->ACC), C660W (TGC-->TGG), H562Y (CAC-->TAC), and A606T (GCC-->ACC), and a heterozygous and a homozygous mutation in codon P664L (CCG-->CTG) as well as a homozygous large deletion of exons 6 to 8. The FH homozygotes manifested generalized xanthomatosis. One of the mutations we identified (C660W) was novel. In conclusion, we identified 5 missense mutations and 1 large deletion in LDLR gene, including 1 novel mutation in Han Chinese with FH in Taiwan.

Insulin is known to cause an increase in endothelin-1 (ET-1) receptors in vascular smooth muscle cells (SMCs), but the effect of insulin-like growth factor 1 (IGF-1) on ET-1 receptor expression is not known. We therefore carried out the present study to determine the effect of IGF-1 on the binding of ET-1 to, and ET type A receptor (ETAR) expression and ET-1-induced 3H-thymidine incorporation in, vascular SMCs. In serum-free medium, IGF-1 treatment increased the binding of 125I-ET-1 to SMC cell surface ET receptors from a specific binding of 20.1%+/-3.1% per mg of protein in control cells to 45.1%+/-8.6% per mg of protein in cells treated with IGF-1 (10 nM). The effect of IGF-1 was dose-related, with a significant effect (1.4-fold) being seen at 1 nM. The minimal time for IGF-1 treatment to be effective was 30 min and the maximal effect was reached at 6 h. Immunoblotting analysis showed that ETAR expression in IGF-1-treated cells was increased by 1.7-fold compared to controls. Levels of ETAR mRNA measured by the RT-PCR method and Northern blotting were also increased by 2-fold in IGF-1-treated SMCs. These effects of IGF-1 were abolished by cycloheximide or genistein. Finally, ET-1-stimulated thymidine uptake and cell proliferation were enhanced by IGF-1 treatment, with a maximal increase of 3.2-fold compared to controls. In conclusion, in vascular SMCs, IGF-1 increases the expression of the ET-1 receptor in a dose- and time-related manner. This effect is associated with increased thymidine uptake and involves tyrosine kinase activation and new protein synthesis. These findings support the role of IGF-1 in the development of atherosclerotic, hypertensive, and diabetic vascular complications., (Copyright (c) 2004 Wiley-Liss, Inc.)

Objective: To identify MEN1 gene mutations and characterize clinical manifestations in Chinese kindred with multiple endocrine neoplasia type 1 (MEN1) in Taiwan., Patients and Methods: Eight unrelated subjects (one male and seven females, age range 26-70 years) with clinical manifestations of MEN1 were analysed. In addition, 45 relatives that included 10 affected (three males and seven females, age range 32-53 years) and 35 unaffected (17 males and 18 females, age range 15-80 years) subjects were evaluated. Genomic DNA extraction, polymerase chain reaction (PCR) and DNA sequence analysis were performed according to standard procedures., Results: We identified heterozygous MEN1 gene mutations in all eight probands and 10 affected subjects as well as in 13 clinically asymptomatic relatives. Novel mutations included a missense mutation in a heterozygous mutation in exon 9 (GAC --> CAC) resulting in a substitution of aspartic acid by histidine at codon 418 (family 1); a nonsense mutation at codon 556 of exon 10 (GAG --> TAG) resulting in a stop codon and termination (family 2); a missense mutation in exon 2 (GGG --> GAG) causing the substitution of glycine by glutamic acid at codon 110 (family 3); and a deletion/insertion mutation in nucleotide 1200 of exon 8 resulting in frameshift and early termination (family 4). Affected subjects in families 5-7 shared the same C insertion at nucleotide 1650 of exon 10, similar to that previously described as a hotspot for mutation, and proband 8 had a previously described mutation in intron 4 of the MEN1 gene (IVS4-9 G --> A). We also found that 18 (58%) of our 31 MEN1 mutant carriers had clinical symptoms, whereas four (13%) had biochemical abnormalities without clinical symptoms, and nine (29%) were unaffected both clinically and biochemically., Conclusions: We have identified four novel mutations in the MEN1 gene in patients with MEN1 in Taiwan.

Background: The causes of neonatal transient hypothyroidism (NTH) remain incompletely understood. Whether it is influenced by genetic background is rarely discussed and remains unproven. A defect in thyroid peroxidase is a common cause of dyshormonogenesis of the thyroid gland in Taiwanese, with a novel mutation (2268insT) present in nearly 90% of alleles studied., Objective: To determine if the presence of this common mutation is associated with NTH in Taiwan., Methods: A mismatched primer was designed and used for this specific 2268insT mutation to screen 1000 normal babies and 260 babies with confirmed NTH., Results: The carrier rate for 2268insT in normal babies (1/200) was significantly lower than in babies with NTH (1/13; p<0.0001)., Conclusions: The results strongly suggest that the presence of this thyroid peroxidase mutation contributes to the development of NTH. Likely pathogenetic explanations include the effect of the stress of extrauterine adaptation during labour on an immature pituitary-thyroid axis in genetically predisposed individuals, combined with environmental triggers such as iodine deficiency, perinatal iodine exposure, and/or goitrogen contamination.

Objective: In the U.K. Prospective Diabetes Study, A1C increased from 1.2 to 1.7% and fasting plasma glucose from 1.0 to 2.8 mmol/l over 10 years in type 2 diabetic patients. It is not known whether the blood glucose increase observed in long-term studies of type 2 diabetes results from small, steady increases throughout the year or from increases during discrete periods., Research Design and Methods: To estimate the variation of actual glycemic control and its relation to holiday times, we measured A1C and fructosamine in 110 patients with type 2 diabetes. These measurements were performed four times at intervals of 4-6 weeks; therefore, glycemic change was determined for three periods: preholiday period (from between November 13 and December 20 to between December 20 and January 20), holiday period (from between December 20 and January 20 to between January 28 and February 28), and postholiday period (from between January 28 and February 28 to between March 1 and April 10). A final measurement of A1C was obtained from 90 subjects in the following December or January., Results: The mean A1C increased, but not significantly, during the preholiday (increase 0.135 +/- 0.723%, P = 0.055) and holiday (increase 0.094 +/- 0.828%, P = 0.239) periods. The mean A1C decreased, but not significantly, during the postholiday period (decrease 0.022 +/- 0.588%, P = 0.695). Altogether, the A1C change during these three periods increased significantly (increase 0.207 +/- 0.943%, P = 0.024). The mean fructosamine increased significantly during the preholiday period (increase 0.151 +/- 0.460 mmol/l, P = 0.001), but there was no significant change during the holiday period (increase 0.057 +/- 0.593 mmol/l, P = 0.321). However, fructosamine decreased significantly during the postholiday period (decrease 0.178 +/- 0.448 mmol/l, P < 0.001). Altogether, the fructosamine changes during the study periods showed no significant difference (increase 0.030 +/- 0.566 mmol/l, P = 0.579). Between March or early April and the following December or January, there was no additional change in A1C (decrease 0.009 +/- 1.039%, P = 0.935) for the 90 participants who returned for follow-up treatment., Conclusions: The present study demonstrates an influence of winter holidays on the glycemic control of patients who have type 2 diabetes, and this poor glycemic control might not be reversed during the summer and autumn months. Therefore, the cumulative effects of the yearly A1C gain during the winter holidays are likely to contribute to the substantial increase in A1C that occurs every year among type 2 diabetic individuals.

The selective intra-arterial calcium stimulation test has greatly facilitated the precise regionalization of insulinomas smaller than 2 cm, which noninvasive techniques (ultrasound [US], computed tomography [CT], magnetic resonance imaging [MRI]) often fail to localize. This study examined not only the role of the test in the localization of insulinomas, but also the responsiveness of 3 beta-cell peptides (insulin, C peptide, and proinsulin) and their relationship to the degree of differentiation of the tumor cells, using percentage decrease of both proinsulin/insulin (P/I) and proinsulin/C peptide (P/C) ratios after stimulation as indices. Ten consecutive surgically proven insulinoma patients each received an injection of calcium into the arteries supplying the pancreas after standard selective angiography and beta-cell peptide levels were measured in samples taken from the right hepatic vein before and 30, 60, 90, 120, and 180 seconds after each injection prior to operation. After surgery, the expressions of the calcium sensing receptor (CaSR) on the resected tumors were assessed by immunohistochemistry. Intra-arterial calcium stimulation with sampling either for insulin or for C peptide correctly predicted the site of insulinoma in 8 of 9 patients or in 7 of 8 patients if the 2 big malignant insulinomas were excluded; thus, the detection rate of this test was 89% and 88%, respectively. Calcium administration stimulated a marked and prompt release of insulin and C peptide simultaneously. Both peaked within 30 to 60 seconds, then declined gradually thereafter, remaining above the baseline at 180 seconds. The magnitude of increase correlated well with the corresponding percentage decrease of P/I and P/C ratios. The response of proinsulin was much less. Immunohistochemistry demonstrated variable membraneous staining for CaSR in normal pancreatic islets and in about 9% of the total normal beta cells, whereas staining in tumor cells was only minimally detectable. We conclude that selective intra-arterial calcium stimulation with hepatic venous sampling either for insulin or for C peptide is a highly sensitive method for the preoperative localization of small insulinomas. Calcium injection stimulates a brisk response of insulin, C peptide, and proinsulin simultaneously and the magnitude of increase of both insulin and C peptide appears to be correlated well with the degree of differentiation of the tumor cells. The exact mechanism by which calcium provokes the release of beta-cell peptides is less clear and whether the CaSR is involved in the mechanism of its action requires further study.

Introduction: Familial lipoprotein lipase (LPL) deficiency is inherited as an autosomal recessive trait and is characterized by chylomicronemia, eruptive xanthoma, hepatosplenomegaly, and recurrent pancreatitis., Aims and Methodology: Two unrelated Chinese of Han descent with hypertriglyceridemia were enrolled in this study, and another six Han Chinese with no family history of hypertriglyceridemia and diabetes were recruited as normal controls. LPL activity was determined with use of an artificial substrate of 14C-trioleine and Arabic gum, and release of 14C free fatty acid was determined by the liquid-liquid partitioning system. LPL mass was measured by enzyme immunoassay. Genomic DNA was extracted from EDTA-preserved whole blood, and PCR was used to amplify the nine coding exons and the minimal promoter of the LPL gene., Results: DNA sequence analysis revealed that mutations were identified in both patients; one patient had compound heterozygous mutations in codon 252 [CTG(Leu) --> GTG(Val)] and in codon 264 [TGC(Cys) --> TGa(Ter)] of exon 6, and the other patient had homozygous L252V mutation. These subjects had > or =90% reduction in LPL mass and > or =60% reduction in LPL activity., Conclusion: The mutated and truncated LPLs caused hypertriglyceridemia in these patients in Taiwan with hypertriglyceridemia and pancreatitis.

Objective: Thyroxine-binding globulin (TBG) encoded by the TBG gene on chromosome Xq22 is the major transport protein, carrying approximately 75% of circulating T4. Inherited defects in TBG are associated with three phenotypes based on the level of TBG in serum of affected hemizygous males: complete TBG deficiency (TBG-CD), partial TBG deficiency (TBG-PD) and TBG excess (TBG-E). In this study, we report two unrelated Han Chinese males with complete TBG deficiency who carry different mutations in the TBG gene., Patients: Two index cases of Han males who were diagnosed as having TBG deficiency on the basis of undetectable serum TBG and an additional 75 (50 males and 25 females) normal Han Chinese., Measurement: Serum thyroid hormones were measured by chemiluminescent immunoassay, thyroid autoantibodies by an agglutination test, and TSH receptor antibody and TBG by radioimmunoassay. Genomic DNA extraction, polymerase chain reaction (PCR) and DNA sequence analysis of the TBG gene were performed with standard methods., Results: One index case had one missense mutation in his copy of the gene, a G --> A transition in codon 52 that results in the replacement of serine by asparagine, and a known polymorphism in codon 283 (TTG --> TTt) that results in the replacement of leucine by phenylalanine. The allelic frequency of TBG-Poly allele in 75 normal Han Chinese (100 chromosomes) was 31%. A second index case was hemizygous for a nonsense mutation in codon 280 of exon 3 (TGG --> TGa). This mutation, located in the C-terminal of TBG, predicts a markedly truncated protein., Conclusions: This is the first report of complete thyroxine-binding globulin deficiency (TBG-CDT1 and TBG-CDT2) due to TBG gene mutations in Taiwan.

Although involvement of the adrenals by malignant lymphoma is common, primary adrenal lymphoma is extremely rare. Herein, we report a case of a 59-year-old woman with bilateral adrenal glands enlargement found incidentally on abdominal imaging. Despite of the huge size of the tumor, her adrenal function was intact. Ultrasound-guided biopsy disclosed a picture of malignant lymphoma, diffuse large B cell type. The patient received bilateral adrenalectomy and adjuvant chemotherapy, but succumbed 6 months later. We suggest that, although rare, primary adrenal lymphoma should be considered as a possible cause of bilateral adrenal incidentalomas.